Analysis of novel in vivo derived Plasmodium falciparum transcriptional profiles

摘要 感染疟原虫恶性疟原虫导致广泛不同的临床症状， 儿童状况  从轻微的流感样症状到昏迷甚至死亡尽管 巨大的医学意义，这种多样性的遗传和分子基础仍然存在， 大部分未知。我们假设寄生在人类宿主体内的寄生虫需要 适应这种特殊的环境，在温度，底物和免疫 反应为了表征寄生虫生物学，我们利用了对寄生虫的全基因组分析。 从受感染病人的新鲜血液样本中提取寄生虫。通过这种方法， 确定了寄生虫在人类宿主中的三种生物状态。之一 这些体内状态与实验室生长的转录谱高度相关， 我们已经确定了两个新的状态。这些状态的生物学基础可以解释为 通过与酵母中表达数据的广泛纲要比较， 酿酒酵母体内的三种状态非常类似于（i）活跃生长 基于糖酵解代谢的“体外样状态”;（ii）饥饿反应 伴随氧化磷酸化;和（iii）环境应激反应。的 结果揭示了以前未知的在体内生物学的生理多样性， 疟疾寄生虫，特别是，在无性阶段的功能线粒体的证据 寄生虫，并指出在体内和体外研究，以确定如何这种变化可能会影响 疾病的表现和治疗。这项工作突出了与 人类样本，以探索临床相关的寄生虫生物学。通过进一步的临床 研究我们建议1）确定与这些新的相关的宿主因素， 生物学状态2）确定严重疾病中特别发现的寄生虫生物学3）测试 使用体外模型在受控条件下观察寄生虫的环境反应。 我们正在开发一种全新的模型，用于研究宿主与病原体的相互作用， 寄生虫临床研究为体外模型提供信息，相反，该模型的结果 然后可以在临床研究中进行前瞻性测试。此外，我们还开发了 一个由临床疟疾、计算生物学和分子生物学领域的领导人组成的小组，将联合收割机 他们的技能来加深我们对疾病的理解。长期目标是识别寄生虫 生物学，可以有针对性地减少疟原虫的个人和全球健康负担 恶性疟原虫。恶性疟原虫引起的人类感染范围从无症状到 通常导致死亡的严重疾病。为什么有些病人会患上重病 而另一些则完全清楚，仍然知之甚少，这可能与 发生在人类身上的特殊寄生生物学。通过使用基因组学，我们 已经发现了一种全新的寄生虫生物学， 该项目将确定这种新的生物学是否与疾病结果的差异有关。 这项研究汇集了计算生物学和疟疾流行病学的专家， 开发临床相关的寄生虫生物学模型，为疾病干预提供信息， 减少疟疾感染对个人和全球健康的影响。

ABSTRACT Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in children  ranging from mild flu-like symptoms to coma and death. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown. We hypothesize that parasites residing in the human host have needed to adapt to this specialized environment that varies in temperature, substrate and immune response. To characterize parasite biology we have utilized whole genome analysis of the parasite from fresh blood samples of infected patients. With this approach we have identified three biologic states of the parasite when it resides in the human host. One of these in vivo states correlates highly to the laboratory grown transcriptional profile, and now we have identified two novel states. The biological basis of these states can be interpreted by comparison with an extensive compendium of expression data in the yeast, Saccharomyces cerevisiae. The three states in vivo closely resemble (i) active growth based on glycolytic metabolism "the in vitro like state"; (ii) a starvation response accompanied by oxidative phosphorylation; and (iii) an environmental stress response. The results reveal a previously unknown physiological diversity in the in vivo biology of the malaria parasite, in particular, evidence for functional mitochondria in the asexual stage parasite, and point to in vivo and in vitro studies to determine how this variation may impact disease manifestations and treatment. This work highlights the importance of working with human samples to explore clinically relevant parasite biology. Through further clinical studies we propose to 1) identify the host factors that are associated with these novel biologic states 2) identify parasite biology that is specifically found in severe disease 3) test environmental responses of the parasite under controlled conditions using the in vitro model. We are developing a completely novel model for the host pathogen interaction in this parasite. The clinical studies inform the in vitro model and conversely, results of this model can then be tested prospectively in the clinical studies. Furthermore we have developed team of leaders in clinical malaria, computational biology and molecular biology to combine their skills to further our understanding of disease. The long term goal is to identify parasite biology that can be targeted to reduce individual and global health burden of Plasmodium falciparum. Plasmodium falciparum causes infections in humans which range from asymptomatic to highly severe illness often leading to death. Why some patients have severe disease and others are completely well remains poorly understood, and this may be related to specialized parasite biology that occurs in humans. Through the use of genomics, we have identified completely new parasite biology when it resides in humans and this project will determine if this novel biology is related to differences in disease outcomes. This study brings together experts in computational biology and malaria epidemiology to develop clinically relevant models of parasite biology to inform disease interventions to reduce the impact of malaria infection on individual and global health.